The invention relates to humanized antibodies that bind to the amyloid beta peptide (Aβ) and to preventative and therapeutic treatment of conditions associated with the Aβ peptide, such as Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy.
The Aβ peptide in circulating form is composed of 39-43 amino acids (mostly 40 or 42 amino acids) resulting from the cleavage of a precursor protein, amyloid precursor protein (APP). Conversion of Aβ from soluble to insoluble forms with high β-sheet content and its deposition as neuritic and cerebrovascular plaques in the brain appears to be associated with a number of conditions and diseases. Among these conditions and diseases are both pre-clinical and clinical Alzheimer's disease, Down's syndrome, and pre-clinical and clinical cerebral amyloid angiopathy (CAA). Prevention and/or reversal of Aβ deposition are promising methods for treating conditions associated with the Aβ peptide.
Therapeutic agents which may prevent or reverse Aβ deposition include antibodies to Aβ peptide. WO 00/72880 and Bard, F., et al., Nature Med. (2000) 6:916-919 describe significant reduction in plaque in cortex and hippocampus in a transgenic mouse model of Alzheimer's disease when treated using N-terminal fragments of Aβ peptides and antibodies that bind to them, but not when treated with the Aβ 13-28 fragment conjugated to sheep anti-mouse IgG or with an antibody against the 13-28 fragment, antibody 266. N-terminal directed antibodies were asserted to cross the blood-brain barrier and to induce phagocytosis of amyloid plaques based on in vitro studies as well as a subsequent, ex vivo assay (Bard, F. et al., Proc. Natl. Acad. Sci. (2003) 100:2023-2028).
U.S. Pat. Nos. 5,766,846; 5,837,672; and 5,593,846 (which are incorporated herein by reference) describe the production of murine monoclonal antibodies to the central domain of the Aβ peptide. Among antibodies known to bind between amino acids 13 and 28 of Aβ are mouse antibodies 266, 4G8, and 1C2.
It had been previously been found, as described in WO 01/62801, that administration of the mouse antibody 266 (m266) almost completely restores cognition following prolonged periods of weekly administration of the 266 antibody (object memory) in 24-month old hemizygous transgenic mice (APPV717F). It was also observed that peripheral administration of antibody 266 results in rapid efflux of relatively large quantities of Aβ peptide from the CNS into the plasma. Prolonged treatment also resulted in altered clearance of soluble Aβ, prevention of plaque formation, and improvement in cognition, even without necessarily having the features the art teaches are required for an antibody to be effective, namely, reducing Aβ amyloid plaque burden, crossing the blood brain barrier to any significant extent, decorating plaque, activating cellular mechanisms, or binding with great affinity to aggregated Aβ.
In conjunction with disclosing results with a mouse model indicating a therapeutic utility of a 266 antibody, WO 01/62801 also disclosed humanized 266 antibodies. These antibodies contain variations in framework regions surrounding complementary determining regions (CDRs) of antibody m266, as well as two amino acid substitutions at a single position in CDR1 of the m266 light chain. Additional humanized 266 antibodies are disclosed in PCT/US02/21322, in which amino acid substitutions occur at three positions in CDR2 from the heavy chain of antibody m266.
Therapeutically beneficial antibodies that bind to the epitope recognized by m266 will desirably be stable in solution, display favorable pharmacokinetics, and possess affinity toward an epitope formed by amino acids 13 and 28 of Aβ. Thus, there is a need in the art for additional antibodies possessing characteristics similar to or better than m266 which will be efficacious in humans.